Is Treatment of ST-Segment–Elevation Myocardial Infarction Patients With Ticagrelor or Other P2Y 12 Inhibitors Before Primary Percutaneous Coronary Intervention a Strategy Without Benefit?

HomeCirculation: Cardiovascular InterventionsVol. 11, No. 3Is Treatment of ST-Segment–Elevation Myocardial Infarction Patients With Ticagrelor or Other P2Y12 Inhibitors Before Primary Percutaneous Coronary Intervention a Strategy Without Benefit? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Treatment of ST-Segment–Elevation Myocardial Infarction Patients With Ticagrelor or Other P2Y12 Inhibitors Before Primary Percutaneous Coronary Intervention a Strategy Without Benefit? Kurt Huber, MD Kurt HuberKurt Huber From the 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria (K.H.); and Sigmund Freud University, Medical School, Vienna, Austria (K.H.). Originally published16 Mar 2018https://doi.org/10.1161/CIRCINTERVENTIONS.118.006555Circulation: Cardiovascular Interventions. 2018;11:e006555Based on well-investigated pathomechanisms and the hypothesis that an optimal antithrombotic milieu at time of primary percutaneous coronary intervention (pPCI) is mandatory, former and recent guidelines recommend pre-treatment on transfer to the catheter laboratory (cath laboratory) with intravenous anticoagulants, intravenous or buccal aspirin, and perioral P2Y12 inhibitors, whereby the stronger agents prasugrel or ticagrelor should be preferred over clopidogrel.1 The available scientific data, however, do not strongly support these recommendations because respective data for timely pre-treatment in patients with ST-Segment–Elevation Myocardial Infarction (STEMI) do not exist—prasugrel pre-treatment was not specifically tested in patients with STEMI but was ineffective in non ST-elevation acute coronary syndromes patients with more in-hospital bleeding hazards2—and ticagrelor pre-treatment was neutral compared with its administration in the catheter laboratory with the only advantage that definitive stent thrombosis rates were statistically lower at 30 days in pretreated patients (ATLANTIC trial [Administration of Ticagrelor in the Catheterization Laboratory or in the Ambulance for New ST-Elevation Myocardial Infarction to Open the Coronary Artery]).3 Finally, clopidogrel pre-treatment seems to be beneficial, which takes no wonder as clopidogrel has a delayed action because of its inactive structure and the necessity of metabolic activation.4,5See Article by Koul et alIn this issue of Circulation: Cardiovascular Interventions, Koul et al6 present real-world data of ticagrelor-pretreated STEMI patients (n=5438) versus patients receiving ticagrelor in the cath laboratory (n=1995) with a similar outcome as in the ATLANTIC study: The 30-day composite end point of all-cause death, myocardial infarction, and stent thrombosis was neutral between ticagrelor-pretreated and not pretreated patients as were the single secondary end points of the composite end point. Moreover, severe in-hospital bleeding complications were comparable, and only the rate of patients arriving in shock was slightly lower in ticagrelor-pretreated patients.Based on this result, it has to be questioned again (after ATLANTIC) whether administration of ticagrelor should be delayed after coronary anatomy is known and after potential differential diagnoses have been excluded, disease states for which full antiplatelet action is deleterious or not necessary (eg, aortic dissection, Takotsubo syndrome), or when acute coronary artery bypass grafting might be a better option than PCI.Potential Reasons for the Missing Benefit of Early Ticagrelor AdministrationSince first publications about the importance of well-organized and functioning STEMI networks,7–9 such systems of care have been implemented worldwide with the consequence that guideline-recommended time delays from first medical contact until pPCI could be offered to a majority of patients (a maximum of 120 minutes after first medical contact until pPCI is recommended with shorter times for specific subgroups of patients). In patients with STEMI, reabsorption of the stronger oral P2Y12 inhibitors prasugrel and ticagrelor is delayed up to 4 hours, and only a minority of patients exhibits a complete platelet inhibition during pPCI.10 This can be explained either by hemodynamic compromise in patients with STEMI or by the frequent use of morphine or morphine derivatives or both. Interestingly, morphine use had no impact on long-term clinical outcome despite its impact on gastrointestinal drug reabsorption.11 The consequence of a delayed reabsorption is that the full antiplatelet action of oral P2Y12 inhibitors occurs frequently only 2 to 3 hours after the intervention and might help to reduce early stent thrombosis as seen in ATLANTIC. In contrast, this could not be confirmed by the present study in which data about morphine use and the exact timing of ticagrelor intake before cath laboratory are not known. Indirect data analysis suggests that ≈60% of patients received ticagrelor within 1 hour before pPCI.6 Whether the relatively low in-hospital bleeding rate might be explained by an increase in radial versus femoral approach has also not been investigated in the current study.Is the Hypothesis Wrong That an Optimal Platelet Inhibition During pPCI Is a Prerequisite for a Beneficial Outcome?This question sounds revolutionary but can be partially underlined by the fact that fast-acting intravenous antiplatelet agents, such as glycoprotein IIb/IIIa blockers, were not in general successful in patients with STEMI when used pre-hospital: In the prospective randomized FINESSE study (Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events-Angiographic), pre-treatment with abciximab had no effect on ischemic outcomes but led to more periprocedural bleeding.12 In contrast, in the On-TIME-2 trial (Ongoing Tirofiban in Myocardial Evaluation 2) with tirofiban pre-treatment, the positive outcome was seen especially in patients with STEMI of short duration.13The intravenous fast-acting P2Y12 inhibitor cangrelor was tested in stable and unstable patients14 and offers a treatment strategy in P2Y12 inhibitor naive patients with STEMI. Based on pharmacodynamics, it is also possible to add cangrelor in the cath laboratory to ticagrelor-pretreated STEMI patients,15 which might optimize platelet inhibition during PCI and confirm the hypothesis that optimal platelet inhibition during pPCI is mandatory. Such strategy has, however, not been sufficiently investigated to date for efficacy and safety.All STEMIs Are Not AlikeBecause it is difficult to discard a long-term accepted hypothesis one must search for other potential explanations, the missing benefit of early ticagrelor administration in 2 studies might have its reason in the inhomogeneous character of STEMIs: Don't we know that pre-hospital glycoprotein IIb/IIIa administration is best in the early hours of high-risk STEMI patients (On-TIME-2, APEX-AMI [Assessment of Pexelizumab in Acute Myocardial Infarction], EuroTransfer studies)16–18 when a huge part of myocardium can be saved? Accordingly, an optimal antiplatelet action of ticagrelor by early administration might mainly help high-risk patients with STEMI of short duration and longer transfer times.Unfortunately, data about STEMI duration at time of pPCI have not been shown in the elegant paper of Koul et al,6and a potential association of infarct duration and success or failure of ticagrelor pre-treatment cannot be proven.Should Pre-Treatment of STEMI Patients With Ticagrelor Be Avoided?Although 2 studies have not shown the expected effect, it cannot be excluded that a specific subgroup of patients (eg, high-risk, short duration of STEMI) might benefit from early P2Y12 inhibitor administration. Moreover, it cannot be foreseen for the individual situation whether a transfer to the cath laboratory can be performed without longer delay.Accordingly, the current American College of Cardiology/American Heart Association and European Society of Cardiology guideline recommendations1,19 should not be neglected until more information is available.Future studies of optimal timing of ticagrelor and other strong and fast-acting antiplatelet agents should focus on high-risk patients (risk stratification based on anatomy and comorbidities) and infarctions of short duration (within 2–3 hours from onset of pain) in which a beneficial outcome is more likely. Planned studies with a new subcutaneous fast-acting P2Y12 inhibitor (ACT 246475; NCT03384966) administered early after symptom onset might provide new answers.DisclosuresDr Huber received lecture fees from AstraZeneca, Chiesi, Daiichi Sankyo, Eli Lilly, Sanofi Aventis, and The Medicines Company.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Kurt Huber, MD, 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhleminen Hospital, Montleartstrasse 37. A1160 Vienna, Austria. E-mail [email protected]References1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2018; 39:119–177. doi: 10.1093/eurheartj/ehx393.CrossrefMedlineGoogle Scholar2. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P, Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti LO, Vicaut E, Widimsky P; ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes.N Engl J Med. 2013; 369:999–1010. doi: 10.1056/NEJMoa1308075.CrossrefMedlineGoogle Scholar3. Montalescot G, van 't Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, Cantor WJ, Cequier A, Chettibi M, Goodman SG, Hammett CJ, Huber K, Janzon M, Merkely B, Storey RF, Zeymer U, Stibbe O, Ecollan P, Heutz WM, Swahn E, Collet JP, Willems FF, Baradat C, Licour M, Tsatsaris A, Vicaut E, Hamm CW; ATLANTIC Investigators. Prehospital ticagrelor in ST-segment elevation myocardial infarction.N Engl J Med. 2014; 371:1016–1027. doi: 10.1056/NEJMoa1407024.CrossrefMedlineGoogle Scholar4. Bellemain-Appaix A, O'Connor SA, Silvain J, Cucherat M, Beygui F, Barthélémy O, Collet JP, Jacq L, Bernasconi F, Montalescot G; ACTION Group. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.JAMA. 2012; 308:2507–2516. doi: 10.1001/jama.2012.50788.CrossrefMedlineGoogle Scholar5. Zeymer U, Arntz HR, Mark B, Fichtlscherer S, Werner G, Schöller R, Zahn R, Diller F, Darius H, Dill T, Huber K. Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial.Clin Res Cardiol. 2012; 101:305–312. doi: 10.1007/s00392-011-0393-1.CrossrefMedlineGoogle Scholar6. Koul S, Smith JG, Götberg M, Omerovic E, Alfredsson J, Venetsanos D, Persson J, Jensen J, Lagerqvist B, Redfors B, James S, Erlinge D. No benefit of ticagrelor pretreatment compared with treatment during percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention.Circ Cardiovasc Interv. 2018; 11:xxx–xxx. doi: 10.1161/CIRCINTERVENTIONS.117.005528.LinkGoogle Scholar7. Huber K, Gersh BJ, Goldstein P, Granger CB, Armstrong PW. The organization, function, and outcomes of ST-elevation myocardial infarction networks worldwide: current state, unmet needs and future directions.Eur Heart J. 2014; 35:1526–1532. doi: 10.1093/eurheartj/ehu125.CrossrefMedlineGoogle Scholar8. Kalla K, Christ G, Karnik R, Malzer R, Norman G, Prachar H, Schreiber W, Unger G, Glogar HD, Kaff A, Laggner AN, Maurer G, Mlczoch J, Slany J, Weber HS, Huber K; Vienna STEMI Registry Group. Implementation of guidelines improves the standard of care: the Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry).Circulation. 2006; 113:2398–2405. doi: 10.1161/CIRCULATIONAHA.105.586198.LinkGoogle Scholar9. Waters RE, Singh KP, Roe MT, Lotfi M, Sketch MH, Mahaffey KW, Newby LK, Alexander JH, Harrington RA, Califf RM, Granger CB. Rationale and strategies for implementing community-based transfer protocols for primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.J Am Coll Cardiol. 2004; 43:2153–2159. doi: 10.1016/j.jacc.2003.12.057.CrossrefMedlineGoogle Scholar10. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction.Circ Cardiovasc Interv. 2012; 5:797–804. doi: 10.1161/CIRCINTERVENTIONS.112.972323.LinkGoogle Scholar11. Bonin M, Mewton N, Roubille F, Morel O, Cayla G, Angoulvant D, Elbaz M, Claeys MJ, Garcia-Dorado D, Giraud C, Rioufol G, Jossan C, Ovize M, Guerin P; CIRCUS Study Investigators. Effect and safety of morphine use in acute anterior ST-segment elevation myocardial infarction.J Am Heart Assoc. 2018; 7:e006833. doi: 10.1161/JAHA.117.006833.LinkGoogle Scholar12. Ellis SG, Tendera M, de Belder MA, van Boven AJ, Widimsky P, Janssens L, Andersen HR, Betriu A, Savonitto S, Adamus J, Peruga JZ, Kosmider M, Katz O, Neunteufl T, Jorgova J, Dorobantu M, Grinfeld L, Armstrong P, Brodie BR, Herrmann HC, Montalescot G, Neumann FJ, Effron MB, Barnathan ES, Topol EJ; FINESSE Investigators. Facilitated PCI in patients with ST-elevation myocardial infarction.N Engl J Med. 2008; 358:2205–2217. doi: 10.1056/NEJMoa0706816.CrossrefMedlineGoogle Scholar13. Van't Hof AW, Ten Berg J, Heestermans T, Dill T, Funck RC, van Werkum W, Dambrink JH, Suryapranata H, van Houwelingen G, Ottervanger JP, Stella P, Giannitsis E, Hamm C; Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 Study Group. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial.Lancet. 2008; 372:537–546. doi: 10.1016/S0140-6736(08)61235-0.CrossrefMedlineGoogle Scholar14. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events.N Engl J Med. 2013; 368:1303–1313. doi: 10.1056/NEJMoa1300815.CrossrefMedlineGoogle Scholar15. Schneider DJ, Agarwal Z, Seecheran N, Keating FK, Gogo P. Pharmacodynamic effects during the transition between cangrelor and ticagrelor.JACC Cardiovasc Interv. 2014; 7:435–442. doi: 10.1016/j.jcin.2013.08.017.CrossrefMedlineGoogle Scholar16. van 't Hof AW, Ernst N, de Boer MJ, de Winter R, Boersma E, Bunt T, Petronio S, Marcel Gosselink AT, Jap W, Hollak F, Hoorntje JC, Suryapranata H, Dambrink JH, Zijlstra F; On-TIME Study Group. Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial.Eur Heart J. 2004; 25:837–846. doi: 10.1016/j.ehj.2004.04.003.CrossrefMedlineGoogle Scholar17. Huber K, Holmes DR, van 't Hof AW, Montalescot G, Aylward PE, Betriu GA, Widimsky P, Westerhout CM, Granger CB, Armstrong PW. Use of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention: insights from the APEX-AMI trial.Eur Heart J. 2010; 31:1708–1716. doi: 10.1093/eurheartj/ehq143.CrossrefMedlineGoogle Scholar18. Rakowski T, Siudak Z, Dziewierz A, Birkemeyer R, Legutko J, Mielecki W, Depukat R, Janzon M, Stefaniak J, Zmudka K, Dubiel JS, Partyka L, Dudek D. Early abciximab administration before transfer for primary percutaneous coronary interventions for ST-elevation myocardial infarction reduces 1-year mortality in patients with high-risk profile. Results from EUROTRANSFER registry.Am Heart J. 2009; 158:569–575. doi: 10.1016/j.ahj.2009.08.008.CrossrefMedlineGoogle Scholar19. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2013; 127:e362–425. doi: 10.1161/CIR.0b013e3182742cf6.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 2018Vol 11, Issue 3 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.118.006555PMID: 29870388 Originally publishedMarch 16, 2018 KeywordsEditorialsST elevation myocardial infarctionpre-treatmentticagrelorprimary percutaneous coronary interventionPDF download Advertisement SubjectsCatheter-Based Coronary and Valvular InterventionsTreatment